Chronic neuropathic pain is a debilitating disorder which results in significantly impaired quality of life, and its pathogenesis remains poorly understood. A significant number of chronic pain patients report pain that is opposite to where injury occurred, a phenomenon known as mirror-image pain. Identifying critical genetic and functional changes that may precede the onset of this clinical pain would allow for more carefully targeted pharmacological and other therapies. Exposure of cutaneous nociceptors to increased levels of neurotrophic factors, including GDNF, neurturin, and artemin has been shown to induce behavioral heat sensitization as well as heat sensitization of nociceptors in vitro. Prior research in our laboratory has demonstrated that saphenous nerve axotomy, an experimental model of neuropathic pain, is associated with changes in gene expression in the ipsilateral dorsal root ganglia (DRG) and innervated skin, as well as sensitization of C polymodal fibers (which respond to both mechanical and thermal stimuli). Based on findings that there are similar changes in gene expression in the contralateral limb that correlate with observed functional changes in cutaneous nociceptors, our hypothesis is that neurotrophic factor signaling is important to this phenomenon of mirror-image pain. With the studies proposed here, we seek to confirm that changes in protein levels reflect observed changes in gene expression and to characterize in detail the functional changes occurring in contralateral nociceptors. Based on our hypothesis that the overexpression of neurotrophins in the skin potentiates changes in the DRGs that alter the nociceptors sensitivity, we then target specific receptors/channels in the DRGs with in vivo siRNA interference to determine if observed functional changes in the contralateral nociceptors can be prevented. If selective knockdown of specific genes in the contralateral DRGs prevented observed functional changes, then it would suggest that direct injury to nerves is not required for sensitization. Those genes could then be investigated further as potential targets for pharmacological treatment.